The treatment of malignant brain tumors remains ineffective and warrants new approaches. We have shown that drugs that antagonize the action of calmodulin (Cam) inhibit the growth of malignant cells. We have also developed methods to rapidly purify and evaluate the biochemical and pharmacological properties of Cam from normal and malignant tumors. Furthermore, using these methods we have identified potent and novel Cam antagonists, demonstrated their ability to inhibit the growth of C astrocytoma cells and gained insight into their mechanisms of action. These investigations also resulted in the discovery that Cam-antagonists enhanced the inhibitory effect of bleomycin on the growth of malignant cells. We have applied these methods to compare the biochemical and pharmacological properties of Cam from a pilot malignant cell line, the rat C6 astrocytoma, to that of normal rat cerebrum and found similarities. The goal of our present proposal is to expand upon these previous studies in several ways. First, we will screen the biochemical and pharmacological properties of Cam from several human astorcytoma cell lines and from biopsy specimens. Second, we will test the most potent antagonist for their growth inhibitory effect in vitro and in vivo. Next we will take advantage of our previous experience in characterizing Cam and cyclic nucleotide phosphodiesterases to purify and characterize oncomodulin, a recently discovered, tumor-specific, Cam-like protein, which was shown to be a potent promotor of cellular proliferation. Lastly, we will study the combined effect of Cam-antagonists and bleomycin on the growth of both murine and human astrocytoma cell-lines in vitro and in vivo.